Pharmaceutical preparation containing hydrofuramide and method of using it

ABSTRACT

HYDROFURAMIDE CAUSES, ON ORAL ADMINISTRATION, AN INCREASE IN THE CHOLINESTERASE BLOOD LEVEL, AN INCREASE IN THE ALBUMEN LEVEL IN THE SERUM, A LOWERING OF THE BLOOD VISCOSITY, AND AN INCREASE OF THE SPEED OF THE CIRCULATING BLOOD AND THUS HAS PROVED TO BE OF VALUE IN THE THERAPY OF ALL DISORDERS AND DISEASES WHICH ARE ACCOMPANIED BY DECREASED CHOLINESTERASE BLOOD LEVEL, ALBUMEN LEVEL IN SERUM, AND SPEED OF BLOOD FLOW AND INCREASED BLOOD VISCOSITY. DAILY DOSES BETWEEN 0.45 G. AND 1.35 G. AND SINGLE DOSES BETWEEN 0.1 G. AND 1.0 G. AND PREFERABLY BETWEEN 0.3 G. AND 0.45 G. HAVE PROVED TO BE THERAPEUTICALLY EFFECTIVE, FOR INSTANCE, IN ALCOHOLISM, CIRRHOSIS OF THE LIVER, ANGINA PECTORIS, HYPOTHYREOSIS, POLYCYTHEMIA, ARTERIOSCLEROSIS, AND OTHERS.

United States Patent 3,565,560 PHARMACEUTICAL PREPARATION CONTAININGHYDROFURAMIDE AND METHOD OF USING IT Frederick W. Proewig, 3359 DemottPlace, Wantagh, N.Y. 11793 No Drawing. Filed July 16, 1968, Ser. No.745,109 Int. Cl. A61k 27/00 US. Cl. 424-285 6 Claims ABSTRACT OF THEDISCLOSURE Hydrofuramide causes, on oral administration, an increase inthe cholinesterase blood leevl, an increase in the albumen leevl in theserum, a lowering of the blood viscosity, and an increase of the speedof the circulating blood and thus has proved to be of value in thetherapy of all disorders and diseases which are accompanied by decreasedcholinesterase blood level, albumen level in serum, and speed of bloodflow and increased blood viscosity. Daily doses between 0.45 g. and 1.35g. and single doses between 0.1 g. and 1.0 g. and preferably between 0.3g. and 0.45 g. have proved to be therapeutically effective, forinstance, in alcoholism, cirrhosis of the liver, angina pectoris,hypothyreosis, polycythemia, arteriosclerosis, and others.

BACKGROUND OF THE INVENTION (1) Field of the invention The presentinvention relates to pharmaceutical compositions and more particularlyto pharmaceutical compositions containing hydrofuramide, and to a methodof using such compositions in therapy.

(2) Description of the prior art Nachmansohn stated Withoutcholinesterase there is no life. cholinesterase is unique among all theenzymes as being ubliquitous and of multipurpose action. Cholinesteraseis found in all blood-cells as well as in the blood serum, in themembranes of every cell, at the junction (synapse) of nerve cells.Margaret Greig and coworkers published scientific data of theirinvestigations showing that the permeability of cells and moreparticularly their membranes, i.e. the exchange between blood and bodycells is based upon the acetylcholine-cholinesterase balance and thatthe functioning of this balance is responsible for the cation separationbetween body fluid and cell interior and for the fact that the sodium:potassium equilibrium of the serum is reversed within the cells of thebody. (Greig et al. Arch. Biochem. vol. 23, page 370 (1949); Brit. J.Pharmacol. vol. 5, page 461 (1950); J. Pharmacol. and exp. Therap. vol.102, No. 1, page 19 (1951); Am. J. Physiol, vol. 170, page 339 (1952);Arch Biochem. vol. 26, page 151 (1951).) g

It is now clinically well established that the cholinesterase level ofthe blood is constant and that 75 to 80 units are normal for healthyindividuals. It was found through testing that chronic debilitatingdiseases (cirrhosis of the liver, chronic nephritis) tend to regulatethe cholinesterase level downward. The lowest levels, around 40 units orslightly lower, are found in cancer victims. On the other Patented Feb.23, 1971 have it fixed at a high level. The higher the level, the betteris the exchange of metabolites between blood serum and body cells andnerve action, the easier is the oxygen transport across the bloodzcellbarrier. This increased supply and cellular exchange of substances formetabolic and anabolic purposse, for cellular repair and for respirationis of importance for the well being especially of elderly persons.Therefore, it is of great clinical importance to provide the medicalprofession with a preparation which causes a substantial increase in thecholinesterase blood level.

SUMMARY OF THE INVENTION Now it is one object of the present inventionto provide a highly effective pharmaceutical composition which increasesthe cholinesterase blood level considerably more than heretoforepossible.

Another object of the present invention is to provide a method oftherapeutically increasing the cholinesterase blood level and thus tofavorably affect these disorders and dieases in which theacetylcholine-cholinesterase equilibrium is reduced.

Other objects of the present invention and advantageous features thereofwill become apparent as the description proceeds.

In principle the compositions according to the present inventioncontain, as the cholinesterase blood level increasing agent,hydrofuramide, i.e. N,N-di-2-furfurylidene-Z-furfurylidene diamine ofthe formula This compound has a melting point of 117 C. It is obtainedby reaction of furfural with aqueous ammonia. It is relatively stableand is decomposed into furfural and ammonia only by boiling in water.

It was found that oral administration of hydrofuramide results in asubstantial increase in the cholinesterase level in the blood. As aresult thereof the albumen level in serum is also increased. This is ofclinical value, for instance, in the treatment of liver cirrhosis inwhich the serum albumen is low.

Furthermore, the viscosity of the blood is lowered, a reaction ofhydrofuramide. No other drug is known at present to have such actionwith the exception of the thyroid hormone. Lowering of blood viscosityleads to better circulation demonstrated by a decrease of the Decholintime. This test is used for measuring blood viscosity. About 11 secondsis the time in normal persons within which the intravenouslyadministered drug Decholin is felt as bitter taste on the tongue. Thistime increases to 30 seconds or more with an increase in viscosity. Theviscosity itself can be tested by means of viscosimeters such as the onedesigned by Hess. Normal values for the blood vicosity are 3.5 to 3.7.The viscosity may be increased to 5.5 or higher, i.e. to values at whicha cardiac thrombosis is threatened. The increase of viscosity goes hand,patients with compensated heart condltlons and having mild polycythemiatend to be higher than normal in their cholinesterase levels.

Various clinical investigators all over the world have tried to induce arise in cholinesterase levels through drugs, enzymes, hormones,radiation etc. The maximum thus achieved was an elevation of 5 units.The acetyl choline-cholinesterase equilibrium acts in an analogousmanner as, for instance, metabolism. It is desirable to hand In handwith an increase of red blood cell counts and globulin in the serum. Forinstance, a hemoglobin value of 17.5 g. percent instead of the normalcontent of 14.5 g. percent is accompanied by an increase in viscosity to5.5. When orally administering hydrofuramide in small doses of 0.4 g. to0.7 g. daily, the high viscosity value of 5.5 will be lowered to 3.7within three Weeks. This has proved of value in the treatment of anginapectoris, for instance.

Lowering of the viscosity by administration of hydrofuramide causes alsoan increase in the speed of circulation of the blood, i.e. a decrease ofthe circulation time. Thus when through lowering of the blood viscositythe initially determined circulation time of 22 seconds is lowered to 11seconds, it is evident that twice the amount of oxygen within the sameperiod of time is offered to all body cells.

As a result of the increase of the blood chlolinesterase level and theaccelerated blood flow, the exchange of metabolites will be improved andthe blood supply to starving organs will be restored almost to normalcy.The increased cholinesterase content of the blood facilitates theexchange from blood to cell and the decreased blood viscosity aboutdoubles the blood supply to the body cells. Thus hydrofuramideadministration surpasses in its effectiveness upon angina pectoris eventhe effect of nitro compounds. Patients, after being put onhydrofuramide, have discontinued using either long acting or immediatelyacting nitro compounds. Fading memory and disorientation in elderlypersons becomes normal. Symptoms secondary in diabetes are eliminated.Intermittent claudicatio, Menieres disease, paresthesias, pruritus,irrespectively whether these symptoms are caused by diabetes orarteriosclerosis, are markedly improved.

The same beneficial effect of hydrofuramicle with respect to circulationobserved in cases of angina pectoris were also observed in other cardiacconditions such as tachycardia or extrasystoles. Hydrofuramide given inamounts of 0.4 g. to 0.7 g. daily eliminates extrasystoles even afterthree years duration, whereas textbooks on cardiology state thatextrasystoles persisting longer than one and half years cannot beinfluenced therapeutically any more.

The fiow of blood accelerated by administration of hydrofuramide and theincreased exchange of oxygen favorably affects even severe cases ofemphysema. Although results observed here are less dramatic than thoseobserved in heart ailments, the patients felt better when takinghydrofuramide and stated that breathing is made easier.

The beneficial effect of cellular respiration and increase in metabolismis seen more particularly in cases of alcoholism. When alcoholicsabstain from drinking, the well known Withdrawal symptoms occur for oneto two weeks, i.e. extreme nervousness, irritation, tremors, andpsychosis. These withdrawal symptoms are never seen when 0.7 g. ofhydrofuramide are given daily. Since under hydrofuramide the switch fromdipsomania to abstinence is not felt at all, it is not necessary to givesuch patients sedatives, tranquilizers, or massive doses of vitamins.The treatment can even be ambulatory. Hospitalization is not required.

Since it has been reported that the ability to learn is greater, thehigher the concentration of cholinesterase in the brain, administrationof hydrofuramide has also a favorable effect on learning children.

Summarizing the effect of administration of hydrofuramide, it has provedeffective (a) in the treatment of alcoholism and cirrhosis of the liverbecause the cholinesterase level as well as the albumin level in theblood are increased;

(b) in the treatment of angina pectoris, multiple sclerosis,hypothyreosis, polycythemia, and diabetes because the high bloodviscosity in these diseases is lowered thus causing at least a markedimprovement;

for preventing intoxicating side effects such as radiation hangoverencountered on X-ray and radiocative cobalt irradiation and forincreasing the tolerated dose of such irradiation;

(d) as highly effective agent for stimulating appetite and for relievingParkinsons symptoms whereby it has a similar effect as furfural but ismuch better tolerated than the latter.

The daily dose of hydrofuramide to be administered is between about 0.3g. and about 2.0 g., the preferred daily dose is between about 0.45 g.and about 1.35 g., the single dose is between about 0.1 g. and about 1.0g. and the preferred single dose is between about 0.30 g. and about 0.45g.

The preparation is orally administered, preferably in the form oftablets, or dragees. Capsules may also be given.

DESCRIPTION OF THE PREFERRED EMBODIMENTS As stated above, hydrofuramideis preferably administered orally in the form of tablets, dragees,pills, lozenges, and the like shaped preparations. Hydrofuramide mayalso be administered in powder form, preferably enclosed in gelatin orthe like capsules. Oral administration in liquid form, such as in theform of emulsions, suspensions, and the like are also possible. Aqueouspreparations, however, cannot be stored over a prolonged period of timebut suspensions, for instance, in edible oils and the like can be used.

Such solid and liquid preparations are produced in a manner known per seof compounding and processing pharmaceutical products whereby theconventional diluting, binding, and/ or expanding agents, lubricants,and/ or other excipients, such as lactose, cane sugar, dextrins, starch,talc, kaolin, magnesium carbonate, pectin, gelatin, agar, bentonite,magnesium stearate, and others may be employed.

The following examples serve to illustrate the present inventionwithout, however, limiting the same thereto.

Example 1 50 kg. of hydrofuramide are intimately mixed with 73.5 kg. oflactose, 10 kg. of corn starch, and 1.5 kg. of magnesium stearate andthe mixture is compressed to tab lets weighing about 405 mg. Each tabletcontains about 150 mg. of hydrofuramide.

Example 2 200 g. of hydrofuramide are mixed with g. of corn starch,moistened with a 5% gelatin solution, and granulated by pressing througha sieve #20. The granulate is dried. g. of potato starch and 30 g. ofpurified talc are thoroughly admixed thereto and the mixture iscompressed to 1000 tablets, each weighing 400 mg. and containing 200 mg.of hydrofuramide.

Example 3 The mixture of hydrofuramide, lactose, corn starch, andmagnesium stearate is compressed to bi-convex dragee cores of 405 mg.These cores are sugar-coated by rotating in a coating pan with sugarsirup. Each dragee contains about mg. of hydrofuramide.

Example 4 Before sugar-coating, the dragee cores obtained according toExample 3 are shellac-coated by means of an alcoholic shellac solution.The finally sugar-coated dragees do not dissolve in the gastric juicesbut only in the intestines. The therapeutic effect, however, is aboutthe same.

Example 5 Hard gelatin capsules are filled each with 300 mg. ofhydrofuramide.

Compositions as described in the examples have been administered topatients in the treatment of various disorders and diseases. Thus 17alcoholics received three times daily 2 to 3 tablets of hydrofuramide,each tablet containing 150 mg. of the active compound. After three daysno alcohol was given. There were no withdrawal symptoms, such as tremor,anorexia, headache, convulsions, and the appetite of the patient wasgood. No additional administration of vitamins, tranquilizers, orsedatives was required.

A case of liver cirrhosis was treated with hydrofuramide. The patient, a53 year old male, was hospitalized because of severe hemorrhages fromvaricose veins of the esophagus. This is usually the last stage in thisdisease. The extremely swollen liver prevents the return of venous bloodfrom the lower end of the esophagus. Varicosities result and these willrupture when sufficiently large. Haemoptoe from the mouth isconsiderable, most patients with esophageal varices bleed to death inthis way. The patients hemoglobin was down to 5.5 g. (normal is 14.5 g);icteric index 45 units (normal 4 to 6 units); albumen 2.0 g. (normal 4.5to 5.5 g.); severely icteric skin, sclerea deep yellow; liver in sizeincreased down to level of navel; considerable ascites, and swelling oflower legs and ankles. After 6 months of treatment with hydrofuramide(0.6 g. daily), the patients icteric index was down to 14 units, whichis considered subicteric. His skin and sclerea were only faintly yellow;his albumen was up to 3.9 g., the hemoglobin 10.5 g. His ascites wascompletely gone together with the swelling of the legs. The patient hasnever experienced any bleeding from the esophagus or throat since hisfirst episode. The liver is down in size to normal below the right lowerrib margin, "but is still increased to he left over the stomach andslightly tender there. Patient is well and working.

A 65 year old male patient has been suffering from angina pectoris forthe past 9 years. He has been treated with long acting tetranitratecompounds, digitalis, and sedation. This well nourished man had toretire from business about 18 months ago after he had gone through ananterior wall infarction. He was given hydrofuramide (0.9 g. daily).After two weeks the patient noticed improvement of the retrosternalpain. The angina attacks occurred less often and the pain wasconsiderably less. After four weeks of treatment the patient was freefrom symptoms. His blood pressure remained the same systolic, 160 mm.Hg, his diastolic pressure, however, was markedly decreased: from 120mm. Hg at the beginning of the treatment it was down to 95 mm. duringthe fifth week. Patients yellowish complexion had changed to healthypinkinsh flush, indicating improved circulation due to widening of thearterioles. After six weeks of hydrofuramide medication all other drugs,nitrates, sedatives, digitalis were discontinued. Patient resumed hisregular work. His. friends remarked that he was looking so much better.He has been working for two years now and has never noticed anginal painwhen working, carrying loads, ascendmg stairs. Patient is now on amaintenance dose of 0.3 g. of hydrofuramide daily.

Other patients suffering from angina pectorls with a decholin time over20 seconds who received hydrofuramide showed a decrease of the decholintlme to near normal (11 seconds), thus indicating an almost doubling ofthe rate of blood flow with a corresponding lowering of blood viscosity.

Another patient was treated for hypothyreos1s and polycythemia. Bothconditions have in common: Red blood cell count about 25% above normal,high viscosity of blood as measured by the viscosimeter after Hess, madeby Hellige. Normal values are 3.5 to 3.6- compared with water. Thispatient, a 25-year-old male, showed viscosity values of 5.5 and higher.He complained about fatigue, frequent headaches, and nosebleeds. Heartand blood pressure were normal. His blood count ranged from 5.4 to 5.7million red cells, his hemoglobin was elevated from 115 to 122%. He wasobserved for 2 years while being treated with occasional phlebotomies.After the patient was given hydrofuramide (0.15 g. three times daily)patients subjective symptoms got gradually better. His blood countremained high. It was not affected by the therapy. The viscosity,however, was reduced to 4.0 to 3.4, an average drop of 1.8 standardvalues, or an average of about one third. As a result thereof, the speedof blood flow was increased and the patient feels less tired. Aftertreatment was begun, patients cholinesterase level increased from 88units to units, further aiding supply and metabolism of body cells.

A 62-year-old male was retired from his job as petroleum engineerbecause of disorientation due to arteriosclerosis. He was unable to workbecause of mental dissociation, slowness of comprehending, andforgetfulness. He had lost weight steadily and exhibited shallowcomplexion. At home he was disturbed to the effect that he got out ofbed at 3 am. pretending that it was breakfast time. He could not selecta telephone number from the book or dial the telephone. He received twotablets of hydrofuramide twice daily, i.e., 0.6 g. per day. Improvementbegan soon after initiation of therapy. After three months he again wasable to attend meetings, he could drive his car, he made no mistakesdialing the telephone. His mind became absolutely clear, he gainedweight (35 lbs. in about six months). He has a healthy complexion andhis friends repeatedly made the statement that he never looked and actedso well in all his life. The increase of cholinesterase in the bloodaccounts for his improvement. The blood-brain barrier is lowered.

Another patient, a 60-year-old male, has been suffering from diabetesfor the past ten years. He received the standard treatment, i.e.,insulin and later Orinase. But he complained of secondary symptoms whichwere not alleviated through diet and medication. He always felt weak,especially in the legs. He noticed cramps in the calves when walking. Hehad tingling in the extremities, occasional itching of the skin. Whengiven hydrofuramide (0.45 g. daily) tiredness and all other symptomsdisappeared during the fourth week of treatment. Patient noticedspecifically that he could walk faster and did not tire anymore. Fastingblood sugar and sugar tolerance, however, were unaffected by the drug.But hydrofuramide evidently eliminates completely the secondary effectsof diabetes mellitus, namely circulatory disturbances, neuritis andtiredness which usually are unaffected by standard medication.

Another patient, a 66-year-old male, was hospitalized because ofmultiple kidney stones causing anuria. The anuria subsided after 36hours following treatment. Patient was discharged three days later withthe advice to be scheduled for later operation for removal of kidneystones. He was given 0.3 g. of hydrofuramide three times daily. Duringthe second week of the treatment patient passed repeatedly numerousstones (calcium. oxalate). Control X-rays two weeks later showed noresidual stones present.

With respect to radiation the following effects of the hydrofuramidetherapy were observed.

(a) The ionization hangover never occurs in patients treated with largedoses of cobalt for malignancy.

(b) Healthy tissue is better protected against radiation damage as canbe demonstrated by the increased tolerance of mice against lethal dosesof radioactive cobalt.

(c) Hydrofuramide evidently interferes with the pathological metabolismof cancer tissue by temporarily inhibiting, or partially inhibiting, thereductive amidation which is specific for cancer tissue. As a resultthereof a lowering of the pH-value in cancer tissue only renders themalignant growth more sensitive to therapeutic radiation.

Thus a female patient suffering from a gynecological cancer, inoperablegrade 4, received cobalt treatment and was given hydrofuramide beforeand during treatment. She never experienced X-ray sickness and felt wellthroughout. On re-examination it was found that the tumor had recededmore than is usual with radiation and laparotomy. It was found atoperation that high up the abdominal aorta some lymphnodes were leftenlarged due to metastases. This area was not reached by the firstseries of radiation with cobalt. So after discharge from the hospitalthe patient received a second series of cobalt treatment also whiletaking hydrofuramide. As a result of this treatment, the patient hasgained weight, feels well, performs all her duties as housewife, etc.These and other case histories show that hydrofuramide has a noteworthyeffect on all disorders and diseases which are due to, or areaccompanied, by a reduced cholinesterase blood level and/ or anincreased viscosity of the blood.

I claim:

1. A method of treating disorders and diseases of human patients in Whomthe acetylcholine-cholinesterase equilibrium is reduced and ofincreasing the cholinesterase level in the blood of such patients, saidmethod comprising orally administering to such patients between about0.3 g. and about 2.0 g. of hydrofuramide daily given in single doses isbetween about 0.1 g. and about 1.0 g.

2. The method of claim 1, wherein the daily dose is between about 0.45g. and about 1.35 g. and the single dose is between about 0.3 g. andabout 0.45 g.

3. The method as defined in claim 1, wherein hydrofurarnide isadministered in tablet form.

4. The method as defined in claim 1, wherein hydrofuramide isadministered in capsule form.

5. The method as defined in claim 2, wherein hydrofuramide isadministered in tablet form.

6. The method as defined in claim 2, wherein hydrofuramide isadministered in capsule form.

References Cited Chem. Albst. (l), 63, 1l935e (1965). Chem. Abst. 2 63,18968a (1965).

STANLEY J. FRIEDMAN, Primary Examiner

